tbuckley/cabot-search huggingface dataset:
NCOG-30. MULTISESSION RADIOSURGERY FOR UNFAVORABLE NONFUNCTIONING PITUITARY MACROADENOMA: 5-YEAR OUTCOMES FROM A SINGLE INSTITUTION PROTOCOL
Authors: Akrita Bhatnagar, Michael Carrasquilla, Vikram Nayar, Brian Collins, Sean Collins, Amjad Anaizi, Joseph Watson, Walter C Jean, Brent Harris, Dylan Conroy, Simeng Suy, Nelya Ebadirad, Edward Aulisi
Journal: Neuro-Oncology (2022)

Abstract Nonfunctioning macroadenoma is a commonly diagnosed pituitary tumor. Resection is the favored treatment, with radiosurgery often utilized for residual or progressing disease. Long-term outcomes are established for single-session radiosurgery, but mature outcomes are lacking for multisession radiosurgery. We report our institution’s 5-year efficacy and safety results for unfavorable nonfunctioning pituitary macroadenoma patients treated with 5-fraction robotic radiosurgery. Between 2010-2020, patients who completed 5-fraction radiosurgery for the treatment of unfavorable nonfunctioning pituitary macroadenomas were included. A tumor was considered unfavorable if the gross tumor volume (GTV) was larger than 5 cc or if it closely approached a critical structure (optic apparatus, brainstem or pituitary gland). Local control was calculated using the Kaplan-Meier Method. RESULTS Twenty predominately female patients (60%), age from 21-77 (median: 53 years) were included in this study. All underwent primary resection. Indications for radiosurgery included unresectable recurrence (85%) and residual disease progression (70%). Median tumor volume was 3.4 cm3 (range: 0.3-20.8 cm3) and 40% of the tumors were suprasellar. A mean dose of 30 Gy (range: 25Gy-30Gy), was delivered to a median isodose line of 80% (range: 75%-89%). Toxicity was minimal with 12 patients (40%) developing acute short-lived headaches and 1 patient (5%) developing a brief ipsilateral 6th nerve palsy. There was no radiation induced optic or pituitary dysfunction identified in this cohort. At a median follow up of 5 years local control at 5 years was 95%. There was 1 in-field failure pathologically confirmed following surgery for pituitary tumor hemorrhage and 2 radiographically confirmed out-of-field failures in patients with large tumors (&amp;gt; 20 cc) treated with lower doses (25 Gy). CONCLUSIONS The treatment of unfavorable nonfunctioning pituitary macroadenoma with 5-fraction robotic radiosurgery provides excellent local control to date, with minimal toxicity. Continued follow-up for the long term optic and pituitary function preservation and tumor control is needed.
IMMU-42. ADOPTIVE HEMATOPOIETIC STEM CELL AND APD1 THERAPY CONVERGE IN THE THYMUS TO PROMOTE ANTI-GLIOBLASTOMA IMMUNITY
Authors: Connor Francis, Laura Falceto Font, John Figg, Bayli DiVita Dean, Mathew Sebastian, Dan Jin, Kaytora Long-James, Christina Von Roemeling, Alexandra Reid, Ginger Moore, Duane Mitchell, Catherine Flores
Journal: Neuro-Oncology (2022)

Abstract Our lab previously published that adoptive hematopoietic stem cell (HSC) therapy administered in conjunction with aPD1 increases median survival in multiple models of CNS malignancies. Tumor-infiltrating lymphocytes (TIL) abundance is independently associated with better outcomes in many cancers. Impressively, approximately 25% of TILs are HSC-derived in early disease. Importantly, we show HSC therapy generates de novo TILs in a thymus-dependent fashion and offer evidence of altered central tolerance following aPD1 therapy, which may permit immune activation against a larger pool of tumor-associated antigens. Therapeutic HSCs were prepared from constitutive GFP-expressing (CD45.2+) and PD1KO (CD45.2+) mice and transferred into CD45.1+ hosts. Sublethal 5Gy total body irradiation was administered day 5 post-intracranial tumor implantation. The next day, 1E6 HSCs from a 1:1 – GFP:PD1KO cocktail were injected intravenously. Descriptive statistics are reported as mean ± SD. Transferred HSCs engraft, expand, differentiate, and migrate to form approximately 25% of the TIL compartment in only 15 days. We found that, 56.2% ± 20.3 of CD3+ TILs display a thymocyte-like CD4+CD8+ (DP) phenotype in early disease, and 43.8% ± 17.4 of these DP-TILs are HSC-derived. Interestingly, DP-TILs were virtually absent in advanced disease 29 days after treatment. At this stage, HSC-derived TILs most commonly fell within the single-positive (SP) TIL subsets, comprising 9.8% ± 5.6 of SP-CD8+ TILs. Notably, HSCPD1KO-derived cells were 4x more abundant amongst SP-CD8 TILs when compared to HSCGFP-derived cells (6.5% vs 1.6%, p &amp;lt; 0.05). SP-CD8 thymocytes were similarly enriched for HSCPD1KO progeny (41.1% vs 24.7%, p &amp;lt; 0.05) which may suggest PD-1 blockade directly promotes thymopoiesis. The privileged maturation of PD1-deficient HSCs is intriguingly reversed when GFP:PD1KO HSCs are co-transferred into non-tumor-bearing mice. Thus, we show the thymus is an active site where PD-1-blocking agents function, and that HSC + aPD1 therapy is uniquely positioned to leverage thymus-dependent anti-tumor immunity.
NIMG-77. MAGNETIC RESONANCE IMAGING AND AMINO ACID POSITRON EMISSION TOMOGRAPHY IN DIFFERENTIATING TUMOR RECURRENCE FROM RADIATION NECROSIS IN HIGH GRADE GLIOMAS
Authors: Arpita Sahu, Ronny Mathew, Archya Dasgupta, Renuka Ashtekar, Ameya Puranik, Epari Sridhar, Ayushi Sahay, Abhishek Chatterjee, Prakash Shetty, Aliasgar Moiyadi, Tejpal Gupta
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND AND PURPOSE Differentiating tumor recurrence (TR) from radiation necrosis (RN) in high grade glioma (HGG) following radiotherapy can be challenging. The ability of conventional magnetic resonance imaging (MRI) to differentiate TR from post-therapeutic effects is often limited. Multiparametric advanced MRI (perfusion) and positron emission tomography (PET) with amino acid tracers, specifically 18F-Fluoroethyl-Tyrosine (FET) can provide relevant additional information on tumor metabolism, which allows for a more accurate diagnosis to differentiate tumor recurrence from radiation necrosis in high grade gliomas. MATERIALS AND METHODS Prospective analysis of 62 lesions in 62 patients with HGG who underwent both MRI and FET-PET imaging within three weeks intervals was done independently by a neuroradiologist and nuclear medicine physician. The study was conducted in a tertiary care oncology center between July 2018 and August 2021. Manually segmented regions of interest were placed over the areas of maximum enhancement/suspicion on MRI and FET uptake, which were used to calculate the relative cerebral volume (rCBV) and tumor to background ratios, respectively. Definitive diagnosis (TR versus RN) was made on clinico-radiological follow-up or histopathological report (wherever available). RESULTS Out of the 62 lesions that were studied, 46 and 16 had TR and RN, respectively. The sensitivity and specificity for determination of TR in HGG with conventional MRI were 98% and 62.5% respectively, while with FET-PET it was 91% and 87.5% respectively. The PPV , NPV and accuracy for MRI were 88%, 91% , 89% , while for FET-PET it was 95%, 78% and 90% respectively. A combination of MRI and PET parameters (mean target-to-background ratio), demonstrated an increase in diagnostic accuracy to 97%. CONCLUSION Cumulative imaging with MRI and FET-PET offers a multiparametric assessment of glioma recurrence that is correlative and complimentary, with higher accuracy and clinical value.
CNSC-13. TUMOR INFILTRATION OF GAMMA-DELTA T CELLS IN GLIOBLASTOMA
Authors: Vilem Juran, Martin Piskacek, Marie Tomandlova, Marek Sova, Martin Smrcka, Tomas Kazda, Vaclav Vybihal, Pavel Fadrus, Andrea Knight
Journal: Neuro-Oncology (2022)

Abstract Gamma-delta (γδ) T cells are innate immunity effector lymphocytes with known prominent anti-tumor reactivity against aggressive glioblastoma (GBM). However, therapeutic approaches have had limited success due to the protective blood-brain-barrier and the immunosuppressive GBM tumor microenvironment. In this study, we determined Vδ1 a Vδ2 γδ T cell populations in peripheral blood and paired tumor tissue samples in patients (n=40) following the resection and throughtout the therapy follow-up. Tumor samples were processed using enzymatic kits and gentleMACSTM Dissociator (Miltenyi Biotec Inc.) and tumor-infiltrating γδ T lymphocytes (TILs) were analyzed by flow cytometry.We found infiltration of both intratumoral CD3+ γδ T cell subsets in 68% tumor samples. We detected Vδ1 γδ T cells in the range 0-0.8% (median 0.26%). Majority of GBM patients presented the Vδ2 subset among TILs in the range 0-13.8% (median 1.5%). Functional studies showed prominent cytotoxicity of magnetically sorted Vδ1 a Vδ2 γδ T cells against GBM cell lines and more importantly against primary tumors. Detailed phenotypic profiling and single-cell sequencing of Vδ2 γδ T cells is currently underway. Next, we identified the EphA2 receptor as one of the targets for tumor-reactive Vδ1 γδ T cells. Specifically, we found that blocking of EphA2 expression resulted in significant inhibition of GBM killing mediated by Vδ1 γδ T cells. Furthermore, Luminex xMAP technology identified significantly elevated levels of stress ligand MICA and check-point inhibitor ligands PD-L1 (B7-H1, CD274) and B7-H3 (CD276) and galectin-9 in patients‘ plasma samples at diagnosis compared to age-matched controls.The patient’s clinical course and therapeutic protocols will be discussed.This study was supported by Ministry of Health, Czech Republic (grant NV19-05-00410 to AK) by Ministry of Health, Czech Republic-conceptual development of research organization (FNBr, 65269705). All rights reserved.
EXTH-15. DRUG SCREENING ON PATIENT GBM CELL CULTURES IDENTIFIES OMACETAXINE MEPESUCCINATE AS A POTENT ANTI-GLIOMA AGENT WITH THE ABILITY TO CROSS THE BLOOD-BRAIN-BARRIER
Authors: Ioannis Ntafoulis, Stijn L W Koolen, Chelsea W J den Hollander, Jie Ju, Trisha Kers, Thierry P P van den Bosch, Kranthi Panth, Laura Mezzanotte, Dana A M Mustafa, Andrew P Stubbs, Clemens M F Dirven, Sieger Leenstra, Martine L M Lamfers
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Little progress has been made in the development of effective new therapies for glioblastoma (GBM) the past decades. Fresh patient-derived GBM cell culture models have become the gold standard for GBM drug discovery and development. One of the major obstacles in identifying novel candidate drugs against GBM remains the blood-brain barrier (BBB). Therefore, it is crucial to select drugs with favourable physicochemical properties to cross BBB and reach the tumour tissue in therapeutically effective concentrations. In current drug repurposing approach, we evaluated available anti-cancer agents in our patient-derived drug screening platform against GBM. METHODS The FDA-approved Oncology Drug Set II library was tested on 45 primary GBM cell cultures. We developed a drug shortlisting pipeline combining efficacy data with pharmacodynamic and pharmacokinetic characteristics of each compound. The therapeutic efficacy of the selected agent was assessed in an orthotopic mouse PDX model, while penetration into the CNS by LC/MS/MS. RESULTS Omacetaxine mepesuccinate (OMA) was ranked as one of the most promising candidates applying our drug selection approach. In vitro, OMA revealed anti-tumour activity at IC50 values well-below reported Cmax plasma values in approximately 80% of GBM cultures. NanoString nCounter analysis, revealed DNA damage repair as the main pathway involved in OMA’s anti-tumour effect. Activation of caspase 3/7 activity and decrease of glioma cell invasiveness were also linked to its anti-tumour effect. In vivo, 1mg/kg dose of OMA was found to reach the brain tumour tissue in concentrations similar to the reported IC50 values in vitro. No adverse reactions were noted and a survival benefit was observed in a proportion of the treated mice. CONCLUSIONS At 1 mg/kg, OMA reaches the tumour brain tissue in therapeutically effective concentrations in mice while a moderate therapeutic benefit was observed. Additional in vivo experiments are ongoing investigating higher dosages of OMA and longer exposure.
BIOM-19. NEXT-GENERATION SEQUENCING (NGS) FOR IDENTIFYING ACTIONABLE MOLECULAR ALTERATIONS IN NEWLY DIAGNOSED AND RECURRENT IDHWT-GLIOBLASTOMA (GBM) PATIENTS: A LARGE MONO INSTITUTIONAL EXPERIENCE
Authors: Marta Padovan, Marta Maccari, Alberto Bosio, Salvatore Vizzaccaro, Ilaria Cestonaro, Martina Corrà, Mario Caccese, Giulia Cerretti, Matteo Fassan, Vittorina Zagonel, Giuseppe Lombardi
Journal: Neuro-Oncology (2022)

Abstract BACKGROUNDNGS panels allow the identification of alterations within hundreds of cancer-related genes and can guide a personalized strategy in glioma treatment. METHODS From Nov 2019 to Jan 2022 at Veneto Institute of Oncology, Padua, Italy, a large cohort of IDHwt-GBM tissues was analyzed by NGS (FoundationOne®CDx). We identified all potential actionable molecular alterations at diagnosis and/or at recurrence. High tumor mutational burden (TMB) was defined as ≥10 mutations/megabase. RESULTS We analyzed 429 IDHwt-GBM samples: NGS profile was available for 419 samples (97.7%); sample failures in 10 cases (2.3%). 351 (84%) and 68 (16%) GBM samples derived from surgery at diagnosis and recurrence, respectively. All patients received radiotherapy and/or temozolomide as first line therapy. Among all the analyzed samples, the most frequent actionable molecular alterations were: CDKN2A (57%), CDKN2B (53%), EGFR amplification (39%), EGFR mutation (24%), PTEN loss (27%), RB1 (23%), NF1 (18%), PIK3CA (18%), CDK4 (15%), MDM2 (10%), PDGFRA (8%), BRCA1-2 (7%), FGFR1-3 (7%), Myc (6%), JAK (6%), ROS1 (5%), METmut (2%), METampl (2%), BRAF V600E (2%). No NTRK1/2/3 druggable alterations were observed. High TMB was found in 18 samples. The incidence of alteration of EGFR (ampl/mut), RB1, PIK3CA was statistically different between the two subgroups of newly diagnosed and recurrent GBM samples (Fisher test). To date, 10% of patients received a personalized treatment as compassionate use, off-label use or in clinical trials (9 Dabrafenib/Trametinib, 8 Alpelisib, 3 Erdafitinib, 2 Ipatasertib, 1 Alectinib, 1 Capmatinib, 1 Palbociclib, 1 Entrectinib, 1 Pamiparib). Activity analysis is still ongoing. CONCLUSIONNGS is feasible in GBM samples. Potentially, a high rate of patients could receive a personalized treatment. The activity analysis is ongoing. However, the incidence of actionable molecular alterations may differ between diagnosis and recurrent GBM samples.
STEM-24. SINGLE-CELL ATLAS OF HUMAN FETAL CEREBELLUM DECODING MEDULLOBLASTOMA ORIGIN AND ONCOGENESIS
Authors: Zaili Luo, Richard Lu
Journal: Neuro-Oncology (2022)

Abstract Medulloblastomas (MBs) are the most common malignant childhood brain tumors, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatment strategies. Previous cell-type analyses of mouse cerebella or human counterparts from frozen tissue nuclei have not fully defined the compositional heterogeneity of MBs. Here, we undertook an unprecedented single-cell profiling of freshly-isolated human fetal cerebella at different developmental stages to establish a reference map for delineating the hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in human fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group-3 and metastatic tumors. Integrated single-cell multi-omic profiling revealed unique regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in aggressive group-3 MBs. Genomic profiling and Hi-C analyses identified de novo long-range chromatin loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group-3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group-3 MB growth. Together, our integrated single-cell atlases of human fetal cerebella and MBs reveal important cell populations predisposed to transformation and regulatory circuitries underlying tumor cell state evolution and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.
NCOG-48. A PROSPECTIVE LONGITUDINAL NEUROCOGNITIVE OUTCOME STUDY IN PATIENTS TREATED WITH CAR-T-CELL THERAPY AT 6 MONTHS
Authors: Giuliana Zarrella, Mitchell Lavoie, Melissa Gardner, Patrick Johnson, Areej El-Jawahri, Michael Parsons
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Chimeric Antigen Receptor T-cell (CAR-T) therapy carries risk of significant neurocognitive function (NCF) toxicities. Longer term NCF outcomes have yet to be reported. The goal of the current study was to assess NCF prospectively in patients undergoing CAR-T. METHODS Adult patients undergoing CAR-T participated in NCF testing with a cognitive clinical trial battery (CTB) at baseline and 6 months after treatment. Group change on each test and on the composite score (CTBC) was examined with paired t-tests and individual change, defined as +/-1 SD on CTBC, was also reported. RESULTS Forty patients (Mage=62.45, 63% male, 97% Non-Hispanic or Latino) completed NCF testing at baseline, and 28 patients completed NCF measures 6 months post-CAR-T (20 complete CTBC, 8 partial CTB, completed virtually). At baseline, 13/40 patients (33%) had significant impairment in NCF (CTBC Z-score &amp;lt; -1.5), and 2/20 (10%) were impaired at follow-up. In the 20 individuals with pre- and 6-month post-CAR-T CTBC scores, there was no significant change (t(19)=-0.926; p=0.366). Examination of each individual test score also showed no changes (immediate memory (t(26)=-0.084; p=0.934), delayed memory (t(26)=-0.207; p=0.837), memory recognition (t (26)=-0.062; p=0.951) executive function (t(18)=-0.447, p=0.660), and verbal fluency (t(27)=-0.035, p=0.972)). Individual analyses of CTBC at follow-up found the number of patients with meaningful decline=1 (5%), improvement=2 (10%), and no change=17 (85%) on CTBC. CONCLUSION Although CAR-T can be associated with acute change in NCF, this prospective longitudinal study showed stable cognitive performance 6 months after treatment. To our knowledge, this is the longest prospective longitudinal study of NCF in CAR-T survivors. This study is limited in that some subjects completed NCF testing virtually at follow-up, limiting the sample size for unconfounded comparison of performance. Future work will examine longer term outcomes and subjective cognitive function in CAR-T survivors.
PATH-33. “GENETIC AND EPIGENETIC PROFILING IDENTIFIES TWO DISTINCT CLASSES OF SPINAL MENINGIOMAS”
Authors: Franz Ricklefs, Krystian Fita, Malte Mohme, Manfred Westphal, Katrin Lamszus, Christian Mawrin, Ulrich Schüller, Sven Eicker
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Spinal meningiomas account for 1.2-12 % of all meningiomas and 25-45 % of all spinal tumours. 20 % of intracranial, but only 4.6 % of spinal meningiomas recur requiring additional treatment. Whereas the classification of intracranial meningiomas has evolved considerably in recent years and uses genetic and epigenetic parameters, the classification of spinal meningiomas is based solely on histopathological findings. By embedding epi-/genetic features, the prognosis of intracranial meningiomas could be significantly improved, which is still lacking for spinal meningiomas. In our work, we integrated genetic and epigenetic parameters into the classification of spinal meningiomas. METHODS We performed epi-/genetic profiling of 50 spinal meningiomas. 497 intracranial meningiomas served as a reference cohort. Copy number variations (CNV) were inferred from the methylation data. Principal component (PCA) and t-SNE analysis were conducted. Clinical and histopathological parameters (location, size, recurrence, WHO°, pathological subtype) were correlated with methylation signatures using the DKFZ brain tumour classifier. RESULTS The methylation signature of spinal meningiomas matched to that of intracranial meningiomas (50/50), although meningioma subgroup assignment was achieved in only 13/50 cases. PCA and t-SNE analysis showed that most spinal meningiomas separate from cranial meningiomas and form two distinct clusters. Cluster 1 matched the methylation class ben-2, while cases in cluster 2 were heterogenous and had a low MSC score. Cases of cluster 1 were located in the upper spine, are more common in males and had an AKT1E17K mutation. NF2 mutations were found mainly in the second cluster, in line with a chr.22 q loss. Interestingly 4 tumors did not associate with the two spinal meningioma clusters and had a particular higher recurrence rate. CONCLUSION Genetic and epigenetic profiling of spinal meningiomas identifies two distinct classes of spinal meningiomas, which may allow an improved prognosis that could lead to a better guidance for adjuvant therapy.
QLTI-13. FEASIBILITY OF SAMEDAY DISCHARGE AFTER BRAIN TUMOR RESECTION: A PROSPECTIVE QUALITY INTERVENTION STUDY
Authors: Frederic Vallejo, Daniel Eichberg, Alexis Morell, Ashish Shah, Long Di, Martin Merenzon, Katherine Berry, Evan Luther, Victor Lu, Nitesh Patel, Dominique Higgins, Michael Kader, Michael Ivan, Ricardo Komotar
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Cranial neurosurgery confers psychological stress, as well as the stress of being in the hospital rather than in one’s preferred surroundings. Compared with inpatient admissions, same-day discharges reduce patient exposure to nosocomial infection, thromboembolic complications, and medical error. Also, it reduces costs to the health care system. OBJECTIVE To report the results of a pilot study that prospectively evaluated for the first time in a United States hospital, the outcomes of patients that underwent brain tumor surgery and are discharged home the same day as surgery. METHODS A quality intervention study including patients who underwent outpatient craniotomy for brain tumors by a single neurosurgeon (R.J.K) at the University of Miami from August 2020 to August 2021 was performed. Patients included were between 16 to 85 years old, with a Karnofsky Performance Status score of ≥ 70, and with supratentorial tumors with a maximum diameter of 4 cm. Complete demographic and clinical data were collected prospectively for each patient. In all patients, the minimum observation period was 6 h after surgery. RESULTS 37 of 334 patients met the inclusion criteria for the outpatient protocol. Thirty-two patients were discharged on the same day as surgery. Five patients (14%) were considered eligible for outpatient surgery but were ultimately admitted to the hospital postoperatively and were discharged after overnight observation. No postoperative complications were noted at two-week follow-up. CONCLUSION With appropriate selection and postoperative monitoring, same-day discharge can be considered a safe and feasible option for certain craniotomy cases. Establishing a multidisciplinary team of physicians, nurses, radiologists, and physical therapists is critical to achieving this aim. Physicians should have a low threshold to admit a patient with concerning exam findings, complications, or complicated past medical history